Cellular senescence and hepatitis B-related hepatocellular carcinoma: An intriguing link

Chronic hepatitis B is mainly responsible for the morbidity and mortality from hepatitis B virus (HBV)-related complications, including hepatocellular carcinoma (HCC) and decompensated cirrhosis. Hepatocellular carcinoma remains the main challenge in the management of not only undiagnosed and/or untreated but also diagnosed and treated patients with chronic HBV infection, as its incidence decreases but is not eliminated even after many years of effective anti-HBV therapy. The exact mechanisms used by HBV to cause malignant transformation remain uncertain, although much of the available data are in favour of a pathogenetic role of HBx protein. Senescence is a cellular state, in which cells lose their ability to proliferate. This biological mechanism may function in a dual mode, namely being both cancer-protective as a result of reduced cellular proliferation, but also cancer-enhancing as a result of modulation of the tissular microenvironment by immune cells during persistent accumulation of senescent cells. Protein X of HBV protein exhibits many similarities in terms of the implemented mechanisms of action and pathways related to the biological process of cellular senescence. Concurrently, insufficient clearance of both senescent and precancerous hepatocytes combined with inadequate immune surveillance as a result of immunosenescence caused by chronic HBV infection may lead to hepatocarcinogenesis. Thus, the effect of HBV seems to be critical as a connecting link between cellular senescence and development of HCC. An ongoing research is underway towards identifying and validating markers of hepatocyte senescence, which could improve the landscape for evaluation of chronic liver disease, thereby providing valuable information in terms of HBV-related carcinogenesis.